Background:Uncovering germline genetic variants responsible for cancer predisposition allows providers to implement personalized medical care for patients. Guidelines were designed to help identify individuals who qualify for genetic testing, yet multiple studies have shown that approximately half of patients with P/LP variants are missed using these guidelines. While guidelines have continued to evolve as more robust data have become available, patients who do not meet these guidelines may not be identified as having a cancer predisposition syndrome. In studies focusing on patients with multiple cancer subtypes, comparisons of universal genetic testing versus guideline-directed for patients revealed a 12.5% likelihood of a pathogenic germline variant. This has also been studied specifically in patients with colorectal cancer, revealing that 15.5% of affected individuals have an identifiable pathogenic variant. As research continues to evaluate universal testing in oncology, it is increasingly evident that we are approaching pathogenic variant carrier frequencies that argue for a more aggressive expansion of guidelines. This has been the catalyst for recommending germline genetic testing for all patients with breast cancer. However, as insurance companies and national guidelines do not yet support this recommendation, here we set out to examine the mutation rate in all patients with breast cancer versus patients with breast cancer diagnosed at or before age 65 years. Methods:Patient data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved multi-center longitudinal, observational study designed to capture genetic and genomic test results and their utilization and impact on treatment practices and outcomes. Descriptive statistics were used to assess and compare data of these populations and germline genetic testing results. Results:Of the 1,302 subjects currently enrolled in the registry, 1,132 have been diagnosed with any cancer type (86.89%), of which 868 have specifically been diagnosed with breast cancer (76.657%). Results indicate that 19.04% of individuals (1 in 4.56) with any cancer type have a germline pathogenic or likely-pathogenic variant associated with cancer predisposition and/or implications for reproduction. Specific to breast cancer, results indicate that 17.74% of individuals (1 in 5.6) harbor a germline pathogenic or likely-pathogenic variant with these same implications. Of the patients with breast cancer, 71.54% were diagnosed prior to age 65 years, while 28.45% were diagnosed at or above age 65 years. 108 patients diagnosed before age 65 years had a P/LP (70.12%) while 46 diagnosed at or above age 65 years had a P/LP variant (29.87%). Conclusion:The iGAP real-world evidence database reveals 17.74% (1 in 5.6) of individuals with breast cancer harbor a pathogenic or likely-pathogenic variant in the germline with implications for medical management and/or reproduction. Given the implications these results can have on patients’ and family members’ health, testing guidelines for breast cancer should be expanded so those with hereditary predispositions can be identified and make informed decisions about preventative measures to reduce risks for a second cancer and overall mortality. Identifying those pathogenic/likely-pathogenic variants also allows for cascade testing of at-risk, likely unaffected relatives, helping reduce overall cancer incidence in the general population. Additionally, since cancer predisposition genes can also confer reproductive implications related to autosomal recessive disorders, expanding testing guidelines can arm patients with additional information that can aid in reproductive decision making. Citation Format: Kelly Bontempo, Chloe Wernecke, Caitlin Mauer, Brenna Bentley, Maureen Graham, Pat Whitworth, Rakesh Patel, Peter Beitsch. Real-world evidence database reveals 17.74% of individuals with breast cancer harbor a germline pathogenic or likely-pathogenic variant with implications for medical management and/or reproduction [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-07-03.

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Background: Each year there are approximately 281,550 new cases of breast cancer.1 With the rise of somatic testing, more physicians are using panels to understand the genetic profile of breast cancer to help aid in clinical management. Agenida, a molecular diagnostics company focused on breast cancer, has developed two tests to support clinical decisions. MammaPrint analyzes 70 genes associated with breast cancer recurrence and reports whether an individual has a low (1.3%) or high (11.7%) risk for recurrence. BluePrint analyzes 80 genes to identify the breast cancer’s molecular subtype: Luminal A (low-risk), Luminal B (high-risk), HER2 (respond well to HER2-targeted therapies), and Basal-Type (aggressive subtype). However, little is known about the relationship between the results of Agendia’s tests and the likelihood of identifying an underlying germline variant. We hypothesize that individuals in the High-Risk category on MammaPrint, and individuals with Basal subtype are more likely to have positive germline genetic results indicating the presence of a pathogenic or likely pathogenic variant. Methods: Patient data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved multi-centered longitudinal, observational study designed to capture genetic and genomic test results and their utilization and impact on treatment practices and outcomes to help determine the most effective use of testing in real-world patient populations and to support access to advances in precision medicine. Of the 1,302 subjects currently enrolled in the registry, 868 have been diagnosed with breast cancer (66.67%). 170 individuals underwent tumor profiling through Agendia’s MammaPrint and BluePrint tests as well as germline genetic testing. Descriptive statistics were used to assess and compare data of these populations. Results: Results indicate that of the 170 individuals who were tested through Agendia’s MammaPrint and BluePrint panels and underwent germline genetic testing, 80 (46.47%) were classified as High-Risk for recurrence on MammaPrint, and 90 (53.53%) were identified as having a Low-Risk for recurrence. Individuals with a high-risk of recurrence had an 18.75% positive germline variant rate compared to the low-risk group with a 12.22% positive rate. 170 individuals with breast cancer were tested and categorized through Agendia’s BluePrint panel. 19 were classified as Basal type, 2 as HER2 type, 90 as Luminal A type, and 50 as Luminal B type. Individuals with Basal type had the highest positive germline rate of 26.32%, compared to HER2 (0%), Luminal A (12.22%), and Luminal B (16.29%).Conclusion: The iGAP real-world evidence database revealed that individuals categorized as having a high risk of breast cancer recurrence through Agendia’s MammaPrint were identified to harbor a pathogenic or likely pathogenic variant 18.75% of the time. An even higher likelihood (26.32%) was seen in individuals with a Basal-Type molecular subtype. This data argues that germline genetic testing should be offered to every individual, regardless of age, identified as having a high risk of breast cancer recurrence and/or a basal-type molecular subtype on Agendia’s tests. Identification of a pathogenic or likely pathogenic variant has clinical management, familial, and potentially reproductive implications. References American Cancer Society, 2021. Citation Format: Brenna G Bentley, Chloe Wernecke, Kelly Bontempo, Maureen Graham, Pat Witworth, Rakesh Patel, Peter Beitsch. Breast cancer patients categorized as high-risk of recurrence and/or basal-type molecular subtype by MammaPrint and BluePrint, respectively, should universally undergo germline genetic testing [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-08-06.

Background:Racial/ethnic disparities in minority access to genetic testing have perpetuated a higher likelihood of identifying an uncertain result in minority populations. Methods:Patient data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved multi-center longitudinal, observational study designed to capture genetic and genomic test results and their utilization and impact on treatment practices and outcomes. Patients self-declare race/ethnicity. Genetic panels contained between 1 and 148 genes and variant classification was determined by the performing genetic testing companies and reported as negative, variant of uncertain significance (VUS), likely-pathogenic, or pathogenic. Descriptive statistics were used to assess and compare data of these populations and germline genetic testing results indicating variant of uncertain significance. Results:Hispanic and African American patients had approximately twice as many uncertain results (VUS) compared to Caucasian patients for all cancer genes examined. Conclusions:Variant adjudication has disproportionately sorted out more uncertain results in Caucasians than Hispanics and African Americans. This leads to greater uncertainty in post-test counseling for these groups and should be a focus for lab testing companies going forward. Citation Format: Peter Beitsch, Chloe Wernecke, Kelly Bontempo, Brenna Bentley, Maureen Graham, Pat Whitworth, Rakesh Patel. Racial and ethnic groups have different clustering of variants of uncertain significance [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-20.

Background: Racial/ethnic disparities in minority access to genetic testing have perpetuated a higher likelihood of identifying an uncertain result in minority populations. Methods :Patient data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved multi-center longitudinal, observational study designed to capture genetic and genomic test results and their utilization and impact on treatment practices and outcomes. Patients self-declare race/ethnicity. Genetic panels contained between 1 and 148 genes and variant classification was determined by the performing genetic testing companies and reported as negative, variant of uncertain significance (VUS),likely-pathogenic, or pathogenic. Descriptive statistics were used to assess and compare data of these populations and germline genetic testing results indicating variant of uncertain significance. Results: The three racial/ethnic groups have similar percentages of BRCA1 and BRCA2pathogenic variants. However, Caucasians have considerably more pathogenic variants in lesser penetrant genes [see Table 1]. Conclusions: Racial/ethnic groups vary by volume of lesser penetrant genes with Caucasians having the highest numbers. Correlation by SNP heritage assignment may lead to a better understanding of these differences. Gene NameAshkenazi PV% Askenazi PVs% of PV subjects AshkenaziAshkenazi VUS%VUS Ashkenazi VUS% of subjects VUS AshkenaziAsian% Asian PVs% of PV subjects AsianAsian VUS%VUS Asian mutations% of subjects VUS AsianBlack/African% Black/African PVs% of PV subjectsBlack/AfricanBlack/African VUS%VUS Black/Africanmutations% of subjects VUSBlack/AfricanCaucasian% Caucasian PVs% of PV subjects CaucasianCaucasian VUS% Caucasian Mutations% of subjects VUS CaucasianHispanic% Hispanic PVs% of PV subjects HispanicHispanic VUS% Hispanic Mutations% of subjects VUS HispanicOther% Other PVs% of PV subjects OtherOther RE VUS% Other RE Mutations% of subjects VUS Other#PV Total% Total PV#VUS TotalBRCA20.00%0.00%0.00%0.00%125.00%25.00%24.17%4.26%531.25%31.25%34.62%4.76%3414.47%16.50%122.42%2.44%815.69%18.18%45.26%5.48%211.11%12.50%36.67%6.82%5014.97%24BRCA1327.27%30.00%0.00%0.00%0.00%0.00%36.25%6.38%318.75%18.75%23.08%3.17%177.23%8.25%91.81%1.83%1631.37%36.36%11.32%1.37%211.11%12.50%24.44%4.55%4112.28%17CHEK20.00%0.00%112.50%12.50%0.00%0.00%12.08%2.13%0.00%0.00%0.00%0.00%2711.49%13.11%51.01%1.02%11.96%2.27%0.00%0.00%15.56%6.25%12.22%2.27%298.68%8ATM19.09%10.00%0.00%0.00%0.00%0.00%510.42%10.64%0.00%0.00%812.31%12.70%218.94%10.19%346.85%6.92%35.88%6.82%911.84%12.33%0.00%0.00%36.67%6.82%257.49%59CHEK2/1100delC19.09%10.00%0.00%0.00%0.00%0.00%12.08%2.13%0.00%0.00%0.00%0.00%104.26%4.85%30.60%0.61%23.92%4.55%22.63%2.74%0.00%0.00%0.00%0.00%133.89%6MUTYH0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%114.68%5.34%51.01%1.02%11.96%2.27%22.63%2.74%15.56%6.25%12.22%2.27%133.89%8PALB20.00%0.00%0.00%0.00%0.00%0.00%12.08%2.13%0.00%0.00%0.00%0.00%72.98%3.40%71.41%1.43%35.88%6.82%11.32%1.37%15.56%6.25%12.22%2.27%113.29%10BLM19.09%10.00%0.00%0.00%0.00%0.00%48.33%8.51%0.00%0.00%34.62%4.76%93.83%4.37%112.22%2.24%0.00%0.00%22.63%2.74%0.00%0.00%0.00%0.00%102.99%20MITF0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%83.40%3.88%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%82.40%0NBN0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%11.54%1.59%83.40%3.88%40.81%0.81%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%82.40%5FH327.27%30.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%41.70%1.94%40.81%0.81%0.00%0.00%11.32%1.37%0.00%0.00%0.00%0.00%72.10%5MSH619.09%10.00%112.50%12.50%0.00%0.00%0.00%0.00%0.00%0.00%4.62%4.76%31.28%1.46%132.62%2.65%23.92%4.55%22.63%2.74%15.56%6.25%0.00%0.00%72.10%19MUTYH-Biallelic/Compound Heterozygous0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%52.13%2.43%10.20%0.20%11.96%2.27%0.00%0.00%15.56%6.25%0.00%0.00%72.10%1MUTYH-Monoallelic0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%16.25%6.25%0.00%0.00%52.13%2.43%0.00%0.00%11.96%2.27%0.00%0.00%0.00%0.00%0.00%0.00%72.10%0PMS219.09%10.00%112.50%12.50%0.00%0.00%0.00%0.00%16.25%6.25%11.54%1.59%52.13%2.43%51.01%1.02%0.00%0.00%33.95%4.11%0.00%0.00%0.00%0.00%72.10%10Other00.00%0.00%562.50%62.50%375.00%75.00%3164.58%65.96%531.25%31.25%4467.69%69.84%6125.96%29.61%38377.22%78.00%1325.49%29.55%4964.47%67.12%950.00%56.25%3475.56%77.27%9127.25%546Grand Total11PV Ash108VUS Ash84PV Asi448Asi VUS4716PV Bla1665VUS Bla63235PV Cau206496VUS Cau49151PV His4476VUS His7318PV Oth1645VUS Oth44334334 PV Mutations Found738 Citation Format: Peter Beitsch, Chloe Wernecke, Kelly Bontempo, Brenna Bentley, Maureen Graham, Pat Whitworth, Rakesh Patel. Racial and ethnic groups have different clustering of common cancer genes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-19.